31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

An emergent Pacific telecommunity : communication policy, process and indicators

M.A. University of Hawaii at Manoa 1981Includes bibliographical references (leaves 148-156).M.A

Sanskrit grammar

xxvi, 551 p.; 23 cm

Determining the influence of past development experience on the cost of strategic ballistic missile development

The influence of learning in the form of past relevant experience was examined in data collected for strategic ballistic missiles developed by the United States. A total of twenty-four new missiles were developed and entered service between 1954 and 1990. Missile development costs were collected and analyzed by regression analysis using the learning curve model with factors for past experience and other relevant cost estimating relationships. The purpose of the study was to determine whether prior development experience was a factor in the development cost of these like systems. Of the twenty-four missiles in the population, development costs for twelve of the missiles were collected from the literature. Since the costs were found to be segmented by military service, a discrete input variable for military service was used as one of the cost estimating relationships. Because there were only two US Navy samples, too few to analyze for segmentation and learning rate, they were excluded from the final analysis. The final analysis was on a sample of ten out of eighteen US Army and US Air Force missiles within the population. The result of the analysis found past experience to be a statistically significant factor in describing the development cost of the US Army and US Air Force missiles. The influence equated to a 0.86 progress ratio, indicating prior development experience had a positive (cost-reducing) influence on their development cost. Based on the result, it was concluded that prior development experience was a factor in the development cost of these systems

Economics and politics

421 p. ; 28 cm[S.l.] : [Dwight W. Learned] , [188-]HolographContents: Political economy. Political scienceAccompanied by "Outline of lectures on Economics and politics. Doshisha College, 1886." (4 p., printed text

Outlines of economics <v. 2>

2 v. ; 22 cm[S.l.] : [D.W. Learned] , [188-]Holograp

Lectures on economics

403 p. ; 28 cm[S.l.] : Dwight W. Learned , 1889HolographAccompanied by "Skeleton of lectures on economics. Dōshisha College, 1889." (19 p., printed text, Yokohama : R. Meiklejohn

The Ornithology of \u27The Century Dictionary\u27

Volume: 8Start Page: 222End Page: 22